title: The C1772T genetic polymorphism in human HIF-1alpha gene associates with expression of HIF-1alpha protein in breast cancer.
abstract: Hypoxia-inducible factor 1 (HIF-1) is an important genetic component involved in the cellular response to hypoxia. HIF-1 is also linked to the regulation of tumor development and growth. In previous studies, the C1772T (P582S) or the G1790A (A588T) polymorphisms of the HIF-1alpha gene have been identified in renal cell carcinoma, head and neck and esophageal squamous cell carcinomas as well as colorectal and prostate cancers. In our study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the expression patterns of HIF-1alpha protein and impact of clinical progression in breast cancer. We also examined the impact of prognosis of HIF-1alpha gene polymorphism and protein expression in the prediction of biological behavior. We performed polymerase chain reaction and direct sequencing to detect polymorphisms in exon 12 of HIF-1alpha from 90 breast cancer patients and 102 healthy controls. The expression of HIF-1alpha was measured in paraffin-embedded specimens from patients by immunohistochemistry. We associated its expression with known prognostic factors. The frequency of the T allele for C1772T in breast cancer patients and healthy controls was 5.6 vs. 4.4%, whereas, the frequency of the A allele for G1790A was 1.7 vs. 4.4%. HIF-1alpha was overexpressed in 56.7% (51 of 90) of the patients. Its overexpression associated with the T1772 polymorphic allele (p=0.04). Elevated levels of HIF-1alpha protein were found in cases of breast cancer with lymph node metastasis (p=0.041), high histological grade (p=0.001) and increased Ki-67 index (p=0.031). These results suggest the potential use of C1772T (P582S) polymorphism and expression analysis in providing a new prognostic factor for unfavorable disease outcomes and may help for clinical decision-making in the treatment of breast cancer patients.
authors.affiliation: Department of Biochemistry and Molecular Biology (BK21 project), Medical Research Center for Bioreaction to Reactive Oxygen Species and Biomedical Science Institute, School of Medicine, Seoul, Korea.
authors.forename: Hye Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Yong Hwa
authors.initials: YH
authors.lastname: Jo
authors.forename: Juhie
authors.initials: J
authors.lastname: Lee
authors.forename: Sang Sook
authors.initials: SS
authors.lastname: Lee
authors.forename: Kyung-Sik
authors.initials: KS
authors.lastname: Yoon
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D046888:Tissue Array Analysis
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit